Abstract
Tamm-Horsfall glycoprotein (THP) is a major glycoprotein associated with human urine that binds pro-inflammatory cytokines and also inhibits in vitro T cell proliferation induced by specific antigens. THP derived from human pregnancy urine (designated uromodulin) has previously been shown to be 13-fold more effective as an inhibitor of antigen-induced T cell proliferation than THP obtained from other sources. Structural analysis of human THP and uromodulin has for the first time revealed that these glycoproteins are O-glycosylated. THP from nonpregnant females and males expresses primarily core 1 type O-glycans terminated with either sialic acid or fucose but not the sialyl Lewis(x) epitope. By contrast, the O-glycans linked to uromodulin include unusual core 2 type glycans terminated with one, two, or three sialyl Lewis(x) sequences. The specific association of these unusual carbohydrate sequences with uromodulin could explain its enhanced immunomodulatory effects compared with THP obtained from males and nonpregnant females. Analysis of THP from one of the pregnant females 2 months postpartum showed a reversion of the O-glycan profile to that found for a non-pregnant female. These data suggest that the glycosylation state of uromodulin could be under the regulation of steroidal hormones produced during pregnancy. The significant physiological implications of these observations are discussed.
Highlights
Tamm-Horsfall glycoprotein (THP) is a major glycoprotein associated with human urine that binds proinflammatory cytokines and inhibits in vitro T cell proliferation induced by specific antigens
To carry out this investigation, uromodulin was isolated from human pregnancy urine by the salt precipitation method previously employed to isolate THP from nonpregnant females and males [2]
This consistent approach to the isolation of THP and uromodulin is important, because uromodulin was originally isolated from human pregnancy urine by a procedure that included lectin affinity chromatography [11]
Summary
Tamm-Horsfall glycoprotein (THP) is a major glycoprotein associated with human urine that binds proinflammatory cytokines and inhibits in vitro T cell proliferation induced by specific antigens. The investigators in this study [18] provided strong evidence that N-linked glycans terminated with GalNAc, and a sulfate group mediates these immunomodulatory activities in vitro This demonstration that THP or its derivative oligosaccharides can mediate cytokine bindings, and specific responses in immune cells suggests that this glycoprotein is functionally equivalent to uromodulin. Several pregnancy associated changes in the glycosylation of THP were found, the most notable being that uromodulin expresses unusual core 2 type O-linked glycans terminated with up to three sialyl Lewisx sequences
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